Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Semaphorins and plexins as therapeutic targets

Nature Reviews Drug Discovery volume 13, pages 603–621 (2014)Cite this article

Subjects

Key Points

  • Semaphorins are membrane-bound or diffusible factors that regulate key cellular functions and are involved in cell–cell communication. Most of the effects of semaphorins are mediated by plexins.

  • Work over the past decade has revealed crucial functions of the semaphorin–plexin system in mammalian physiology. It has also become clear that semaphorins and plexins have important roles in many pathophysiological processes and that they represent novel targets for drugs to prevent or treat various diseases.

  • Several semaphorins and plexins are critically involved in tumour growth and metastasis by controlling tumour development and progression via the formation of autocrine signalling loops in cancer cells, as well as by regulating the interaction of different cells within the tumour.

  • Semaphorins and plexins have also been found to control immune functions by regulating immune cell activation, differentiation and trafficking, and several semaphorins and plexins have crucial roles in inflammatory and autoimmune diseases.

  • Semaphorin 3A and semaphorin 4D have important roles in promoting bone formation and resorption, respectively, and semaphorin 3A and inhibitors of semaphorin-4D-induced signalling have been suggested as potential agents to prevent bone loss.

  • Semaphorin 3A and semaphorin 3E appear to promote particular diseases of the microvasculature, and therapies that target these semaphorins and their downstream signalling events may be promising approaches to treat microvascular diseases.

  • Notably, semaphorin 3A has been suggested to be a critical factor that impedes the regeneration of the central nervous system, and several experimental drugs have been developed to inhibit semaphorin 3A activity in order to promote central nervous system regeneration.

  • Several semaphorins and plexins have been identified as potential targets for drugs to treat particular diseases, such as cancer, immunological disorders, osteoporosis or microvascular diseases. The development of specific ligands or inhibitors is ongoing; indeed, antibodies that are directed against semaphorin 4D are currently being tested in clinical trials.

Abstract

Semaphorins are membrane-bound or diffusible factors that regulate key cellular functions and are involved in cell–cell communication. Most of the effects of semaphorins are mediated by plexins. Work over the past decade has revealed crucial functions of the semaphorin–plexin system in mammalian physiology. It has also become clear that semaphorins and plexins have important roles in many pathophysiological processes, including cancer, immunological diseases and bone disorders, and that they represent novel targets for drugs to prevent or treat various diseases. This Review summarizes the functions of the mammalian semaphorin–plexin system as well as its role in diseases and discusses emerging strategies to pharmacologically target semaphorin–plexin signalling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Semaphorins and their receptors: plexins and neuropilins.
Figure 2: Semaphorin–plexin signalling and binding interfaces.
Figure 3: Some functions of semaphorins and plexins in tumour growth and progression.
Figure 4: Some functions of semaphorins and their receptors in different phases of the immune response.
Figure 5: Some roles of semaphorins and their receptors in bone remodelling.
Figure 6: Structures of xanthofulvin, vinaxanthone and SICHI.

Similar content being viewed by others

References

  1. Semaphorin Nomenclature Committee. Letter to the editor: Unified nomenclature for the semaphorins/collapsins. Cell 97, 551–552 (1999).

    Article  Google Scholar 

  2. Potiron, V., Nasarre, P., Roche, J., Healy, C. & Boumsell, L. Semaphorin signaling in the immune system. Adv. Exp. Med. Biol. 600, 132–144 (2007).

    Article  PubMed  Google Scholar 

  3. Tamagnone, L. et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Pasterkamp, R. J. Getting neural circuits into shape with semaphorins. Nature Rev. Neurosci. 13, 605–618 (2012).

    Article  CAS  Google Scholar 

  5. Gu, C. & Giraudo, E. The role of semaphorins and their receptors in vascular development and cancer. Exp. Cell Res. 319, 1306–1316 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Neufeld, G., Sabag, A. D., Rabinovicz, N. & Kessler, O. Semaphorins in angiogenesis and tumor progression. Cold Spring Harb. Perspect. Med. 2, a006718 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kumanogoh, A. & Kikutani, H. Immunological functions of the neuropilins and plexins as receptors for semaphorins. Nature Rev. Immunol. 13, 802–812 (2013).

    Article  CAS  Google Scholar 

  8. Capparuccia, L. & Tamagnone, L. Semaphorin signaling in cancer cells and in cells of the tumor microenvironment—two sides of a coin. J. Cell Sci. 122, 1723–1736 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Tamagnone, L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell 22, 145–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Kang, S. & Kumanogoh, A. Semaphorins in bone development, homeostasis, and disease. Semin. Cell Dev. Biol. 24, 163–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Negishi-Koga, T. & Takayanagi, H. Bone cell communication factors and Semaphorins. BoneKEy Rep. 1, 183 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pasterkamp, R. J. & Giger, R. J. Semaphorin function in neural plasticity and disease. Curr. Opin. Neurobiol. 19, 263–274 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sakurai, A., Doci, C. L. & Gutkind, J. S. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res. 22, 23–32 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Takamatsu, H. & Kumanogoh, A. Diverse roles for semaphorin-plexin signaling in the immune system. Trends Immunol. 33, 127–135 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Roney, K., Holl, E. & Ting, J. Immune plexins and semaphorins: old proteins, new immune functions. Protein Cell 4, 17–26 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Siebold, C. & Jones, E. Y. Structural insights into semaphorins and their receptors. Semin. Cell Dev. Biol. 24, 139–145 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Hota, P. K. & Buck, M. Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell. Mol. Life Sci. 69, 3765–3805 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Liu, H. et al. Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1. Cell 142, 749–761 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nogi, T. et al. Structural basis for semaphorin signalling through the plexin receptor. Nature 467, 1123–1127 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Janssen, B. J. et al. Structural basis of semaphorin-plexin signalling. Nature 467, 1118–1122 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Perala, N., Sariola, H. & Immonen, T. More than nervous: the emerging roles of plexins. Differentiation 83, 77–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Goshima, Y., Sasaki, Y., Yamashita, N. & Nakamura, F. Class 3 semaphorins as a therapeutic target. Expert Opin. Ther. Targets 16, 933–944 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Nkyimbeng-Takwi, E. & Chapoval, S. P. Biology and function of neuroimmune semaphorins 4A and 4D. Immunol. Res. 50, 10–21 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gherardi, E., Love, C. A., Esnouf, R. M. & Jones, E. Y. The sema domain. Curr. Opin. Struct. Biol. 14, 669–678 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Klostermann, A., Lohrum, M., Adams, R. H. & Puschel, A. W. The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. J. Biol. Chem. 273, 7326–7331 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Koppel, A. M. & Raper, J. A. Collapsin-1 covalently dimerizes, and dimerization is necessary for collapsing activity. J. Biol. Chem. 273, 15708–15713 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Love, C. A. et al. The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nature Struct. Biol. 10, 843–848 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Granja, T. et al. Crucial role of Plexin C1 for pulmonary inflammation and survival during lung injury. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2013.104 (2013).

  29. Zhou, Y., Gunput, R. A. & Pasterkamp, R. J. Semaphorin signaling: progress made and promises ahead. Trends Biochem. Sci. 33, 161–170 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Tran, T. S., Kolodkin, A. L. & Bharadwaj, R. Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol. 23, 263–292 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Janssen, B. J. et al. Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nature Struct. Mol. Biol. 19, 1293–1299 (2012).

    Article  CAS  Google Scholar 

  32. Castellani, V., De Angelis, E., Kenwrick, S. & Rougon, G. Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J. 21, 6348–6357 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Swiercz, J. M., Kuner, R. & Offermanns, S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J. Cell Biol. 165, 869–880 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Giordano, S. et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nature Cell Biol. 4, 720–724 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Casazza, A. et al. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J. Clin. Invest. 120, 2684–2698 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pasterkamp, R. J., Peschon, J. J., Spriggs, M. K. & Kolodkin, A. L. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424, 398–405 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Suzuki, K., Kumanogoh, A. & Kikutani, H. Semaphorins and their receptors in immune cell interactions. Nature Immunol. 9, 17–23 (2008).

    Article  CAS  Google Scholar 

  38. Oinuma, I., Ishikawa, Y., Katoh, H. & Negishi, M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305, 862–865 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Saito, Y., Oinuma, I., Fujimoto, S. & Negishi, M. Plexin-B1 is a GTPase activating protein for M-Ras, remodelling dendrite morphology. EMBO Rep. 10, 614–621 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, Y. et al. Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci. Signal. 5, ra6 (2012).

    PubMed  PubMed Central  Google Scholar 

  41. Gloerich, M. & Bos, J. L. Regulating Rap small G-proteins in time and space. Trends Cell Biol. 21, 615–623 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Swiercz, J. M., Kuner, R., Behrens, J. & Offermanns, S. Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35, 51–63 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Hirotani, M. et al. Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors. Biochem. Biophys. Res. Commun. 297, 32–37 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Aurandt, J., Vikis, H. G., Gutkind, J. S., Ahn, N. & Guan, K. L. The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc. Natl Acad. Sci. USA 99, 12085–12090 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Perrot, V., Vazquez-Prado, J. & Gutkind, J. S. Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J. Biol. Chem. 277, 43115–43120 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Swiercz, J. M., Worzfeld, T. & Offermanns, S. Semaphorin 4D signaling requires the recruitment of phospholipase Cγ into the plexin-B1 receptor complex. Mol. Cell. Biol. 29, 6321–6334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tong, Y. et al. Structure and function of the intracellular region of the plexin-B1 transmembrane receptor. J. Biol. Chem. 284, 35962–35972 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. He, H., Yang, T., Terman, J. R. & Zhang, X. Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration. Proc. Natl Acad. Sci. USA 106, 15610–15615 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang, Y., Pascoe, H. G., Brautigam, C. A., He, H. & Zhang, X. Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin. eLife 2, e01279 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Serini, G., Bussolino, F., Maione, F. & Giraudo, E. Class 3 semaphorins: physiological vascular normalizing agents for anti-cancer therapy. J. Intern. Med. 273, 138–155 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Luchino, J. et al. Semaphorin 3E suppresses tumor cell death triggered by the plexin D1 dependence receptor in metastatic breast cancers. Cancer Cell 24, 673–685 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Tseng, C. H. et al. Sema3E/plexin-D1 mediated epithelial-to-mesenchymal transition in ovarian endometrioid cancer. PLoS ONE 6, e19396 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Roodink, I., Verrijp, K., Raats, J. & Leenders, W. P. Plexin D1 is ubiquitously expressed on tumor vessels and tumor cells in solid malignancies. BMC Cancer 9, 297 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Christensen, C. et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 65, 6167–6177 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Casazza, A. et al. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol. Med. 4, 234–250 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sakurai, A. et al. Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras. Mol. Cell. Biol. 30, 3086–3098 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kigel, B., Varshavsky, A., Kessler, O. & Neufeld, G. Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS ONE 3, e3287 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sabag, A. D. et al. Semaphorin-3D and semaphorin-3E inhibit the development of tumors from glioblastoma cells implanted in the cortex of the brain. PLoS ONE 7, e42912 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Roodink, I. et al. Semaphorin 3E expression correlates inversely with Plexin D1 during tumor progression. Am. J. Pathol. 173, 1873–1881 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Serini, G. et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424, 391–397 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Maione, F. et al. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Invest. 119, 3356–3372 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chakraborty, G., Kumar, S., Mishra, R., Patil, T. V. & Kundu, G. C. Semaphorin 3A suppresses tumor growth and metastasis in mice melanoma model. PLoS ONE 7, e33633 (2012).

  63. Maione, F. et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J. Clin. Invest. 122, 1832–1848 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Casazza, A. et al. Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models. Arterioscler. Thromb. Vasc. Biol. 31, 741–749 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Acevedo, L. M., Barillas, S., Weis, S. M., Gothert, J. R. & Cheresh, D. A. Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111, 2674–2680 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cerani, A. et al. Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1. Cell. Metab. 18, 505–518 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Casazza, A. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Loges, S., Mazzone, M., Hohensinner, P. & Carmeliet, P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15, 167–170 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Bielenberg, D. R. et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J. Clin. Invest. 114, 1260–1271 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kessler, O. et al. Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res. 64, 1008–1015 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Kusy, S. et al. Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells. Neoplasia 7, 457–465 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu, F. et al. Endogenous axon guiding chemorepulsant semaphorin-3F inhibits the growth and metastasis of colorectal carcinoma. Clin. Cancer Res. 17, 2702–2711 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Xiang, R. et al. Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res. 62, 2637–2643 (2002).

    CAS  PubMed  Google Scholar 

  74. Wong, H. K. et al. Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism. Neoplasia 14, 84–94 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Basile, J. R., Castilho, R. M., Williams, V. P. & Gutkind, J. S. Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc. Natl Acad. Sci. USA 103, 9017–9022 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sun, Q., Zhou, H., Binmadi, N. O. & Basile, J. R. Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity. J. Biol. Chem. 284, 32066–32074 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhou, H., Binmadi, N. O., Yang, Y. H., Proia, P. & Basile, J. R. Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression. Angiogenesis 15, 391–407 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhou, H., Yang, Y. H., Binmadi, N. O., Proia, P. & Basile, J. R. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma. Exp. Cell Res. 318, 1685–1698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sierra, J. R. et al. Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J. Exp. Med. 205, 1673–1685 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Segarra, M. et al. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling. Blood 120, 4104–4115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sadanandam, A., Rosenbaugh, E. G., Singh, S., Varney, M. & Singh, R. K. Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis. Microvasc. Res. 79, 1–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Sadanandam, A. et al. Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation. Br. J. Cancer 107, 501–507 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fazzari, P. et al. Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev. Biol. 7, 55 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Worzfeld, T. et al. ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis. J. Clin. Invest. 122, 1296–1305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ye, S. et al. Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion. BMC Cancer 10, 611 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Argast, G. M. et al. Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells. Oncogene 28, 2697–2709 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rody, A. et al. Poor outcome in estrogen receptor-positive breast cancers predicted by loss of plexin B1. Clin. Cancer Res. 13, 1115–1122 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Swiercz, J. M., Worzfeld, T. & Offermanns, S. ErbB-2 and Met reciprocally regulate cellular signaling via plexin-B1. J. Biol. Chem. 283, 1893–1901 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Cagnoni, G. & Tamagnone, L. Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression. Oncogene http://dx.doi.org/10.1038/onc.2013.474 (2013).

  90. Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nature Med. 17, 1473–1480 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Okuno, T. et al. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J. Immunol. 184, 1499–1506 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Fisher, T. E., Smith, E. S. & Zauderer, M. Anti-Sema4D antibodies and epitopes. World Patent WO2013148854 (A1) (2013).

  93. Evans, E. E. et al. Reduction of tumor growth and metastasis by a humanized IgG4 monoclonal antibody to SEMA4D (VX15/2503). Cancer Res. Abstr. 73, (Suppl. 1) 1245 (2013).

    Google Scholar 

  94. Hu, G. & Yu, W. Modulators of Plexin B2 activity. World Patent WO2012135332 (A1) (2012).

  95. Suzuki, K. et al. Semaphorin 7A initiates T-cell-mediated inflammatory responses through α1β1 integrin. Nature 446, 680–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Kikutani, H. & Kumanogoh, A. Semaphorins in interactions between T cells and antigen-presenting cells. Nature Rev. Immunol. 3, 159–167 (2003).

    Article  CAS  Google Scholar 

  97. Kumanogoh, A. et al. Requirement for the lymphocyte semaphorin, CD100, in the induction of antigen-specific T cells and the maturation of dendritic cells. J. Immunol. 169, 1175–1181 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Kumanogoh, A. et al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13, 621–631 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Kumanogoh, A. et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22, 305–316 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Makino, N. et al. Involvement of Sema4A in the progression of experimental autoimmune myocarditis. FEBS Lett. 582, 3935–3940 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Nakatsuji, Y. et al. Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-β therapy in multiple sclerosis. J. Immunol. 188, 4858–4865 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Nylander, A. & Hafler, D. A. Multiple sclerosis. J. Clin. Invest. 122, 1180–1188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nkyimbeng-Takwi, E. H. et al. Neuroimmune semaphorin 4A downregulates the severity of allergic response. Mucosal Immunol. 5, 409–419 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Morihana, T. et al. An inhibitory role for Sema4A in antigen-specific allergic asthma. J. Clin. Immunol. 33, 200–209 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Mogie, G. et al. Neuroimmune semaphorin 4A as a drug and drug target for asthma. Int. Immunopharmacol. 17, 568–575 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Rennert, P. D. et al. T cell, Ig domain, mucin domain-2 gene-deficient mice reveal a novel mechanism for the regulation of Th2 immune responses and airway inflammation. J. Immunol. 177, 4311–4321 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Rice, D. S. et al. Severe retinal degeneration associated with disruption of semaphorin 4A. Invest. Ophthalmol. Vis. Sci. 45, 2767–2777 (2004).

    Article  PubMed  Google Scholar 

  109. Toyofuku, T. et al. Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival. Genes Dev. 26, 816–829 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tsuruma, K. et al. SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 53, 6729–6737 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Nojima, S. et al. A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration. Nature Commun. 4, 1406 (2013).

    Article  CAS  Google Scholar 

  112. Takegahara, N. et al. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nature Cell Biol. 8, 615–622 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Bakker, A. B. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. O'Connor, B. P. et al. Semaphorin 6D regulates the late phase of CD4+ T cell primary immune responses. Proc. Natl Acad. Sci. USA 105, 13015–13020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Takamatsu, H. et al. Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nature Immunol. 11, 594–600 (2010).

    Article  CAS  Google Scholar 

  116. Kang, H. R., Lee, C. G., Homer, R. J. & Elias, J. A. Semaphorin 7A plays a critical role in TGF-β1-induced pulmonary fibrosis. J. Exp. Med. 204, 1083–1093 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gan, Y. et al. Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease. Arthritis Rheum. 63, 2484–2494 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. De Minicis, S. et al. Semaphorin 7A contributes to TGF-β-mediated liver fibrogenesis. Am. J. Pathol. 183, 820–830 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kang, S. et al. Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via αvβ1 integrin. J. Immunol. 188, 1108–1116 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Czopik, A. K., Bynoe, M. S., Palm, N., Raine, C. S. & Medzhitov, R. Semaphorin 7A is a negative regulator of T cell responses. Immunity 24, 591–600 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Catalano, A. et al. Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 107, 3321–3329 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Catalano, A. The neuroimmune semaphorin-3A reduces inflammation and progression of experimental autoimmune arthritis. J. Immunol. 185, 6373–6383 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Wen, H., Lei, Y., Eun, S.-Y. & Ting, J. P. Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J. Exp. Med. 207, 2943–2957 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wanschel, A. et al. Neuroimmune guidance cue Semaphorin 3E is expressed in atherosclerotic plaques and regulates macrophage retention. Arterioscler. Thromb. Vasc. Biol. 33, 886–893 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shimizu, I. et al. Semaphorin 3E-induced inflammation contributes to insulin resistance in dietary obesity. Cell. Metab. 18, 491–504 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Del Fattore, A., Teti, A. & Rucci, N. Bone cells and the mechanisms of bone remodelling. Front. Biosci. (Elite Ed.) 4, 2302–2321 (2012).

    Article  Google Scholar 

  127. Hayashi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Kular, J., Tickner, J., Chim, S. M. & Xu, J. An overview of the regulation of bone remodelling at the cellular level. Clin. Biochem. 45, 863–873 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Fukuda, T. et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature 497, 490–493 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Dacquin, R. et al. Control of bone resorption by semaphorin 4D is dependent on ovarian function. PLoS ONE 6, http://dx.doi.org/10.1371/journal.pone.0026627 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Fukushima, Y. et al. Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. J. Clin. Invest. 121, 1974–1985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Moriya, J. et al. Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis. Circ. Res. 106, 391–398 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Geretti, E., Shimizu, A. & Klagsbrun, M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis 11, 31–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  134. Rivera, J. C. et al. Microglia and interleukin-1β in ischemic retinopathy elicit microvascular degeneration through neuronal semaphorin-3A. Arterioscler. Thromb. Vasc. Biol. 33, 1881–1891 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Fawcett, J. W., Schwab, M. E., Montani, L., Brazda, N. & Muller, H. W. Defeating inhibition of regeneration by scar and myelin components. Handb Clin. Neurol. 109, 503–522 (2012).

    Article  PubMed  Google Scholar 

  136. Pasterkamp, R. J. & Verhaagen, J. Semaphorins in axon regeneration: developmental guidance molecules gone wrong? Phil. Trans. R. Soc. 361, 1499–1511 (2006).

    Article  CAS  Google Scholar 

  137. Okano, H. et al. Therapeutic agent for corneal sensory nerve damage containing semaphorin inhibitor as active ingredient. World Patent WO2012115182 (A1) (2012).

  138. Kikuchi, K. et al. In vitro and in vivo characterization of a novel semaphorin 3A inhibitor, SM-216289 or xanthofulvin. J. Biol. Chem. 278, 42985–42991 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. Masubuchi, M., Okuda, T. & Shimada, T. Antifungal agent, its preparation and microorganism therefor. European Patent EP0537622 (A1) (1993).

  140. Gammon, G. et al. A fungal metabolite which inhibits the interaction of CD4 with major histocompatibility complex-encoded class II molecules. Eur. J. Immunol. 24, 991–998 (1994).

    Article  CAS  PubMed  Google Scholar 

  141. Kaneko, S. et al. A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nature Med. 12, 1380–1389 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Omoto, M. et al. The semaphorin 3A inhibitor SM-345431 accelerates peripheral nerve regeneration and sensitivity in a murine corneal transplantation model. PLoS ONE 7, e47716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Maeda, M. et al. Preparation for treatment of spinal cord injury. European Patent EP2601948(A1) (2011).

  144. Montolio, M. et al. A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration. Chem. Biol. 16, 691–701 (2009).

    Article  CAS  PubMed  Google Scholar 

  145. Shim, S. O. et al. PlexinA2 limits recovery from corticospinal axotomy by mediating oligodendrocyte-derived Sema6A growth inhibition. Mol. Cell. Neurosci. 50, 193–200 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Taniguchi, M. et al. Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron 19, 519–530 (1997).

    Article  CAS  PubMed  Google Scholar 

  147. Behar, O., Golden, J. A., Mashimo, H., Schoen, F. J. & Fishman, M. C. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 383, 525–528 (1996).

    Article  CAS  PubMed  Google Scholar 

  148. Bouvree, K. et al. Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation. Circ. Res. 111, 437–445 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Falk, J. et al. Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron 48, 63–75 (2005).

    Article  PubMed  Google Scholar 

  150. Feiner, L. et al. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 128, 3061–3070 (2001).

    CAS  PubMed  Google Scholar 

  151. Reidy, K. & Tufro, A. Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk. Pediatr. Nephrol. 26, 1407–1412 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Katz, T. C. et al. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev. Cell 22, 639–650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Degenhardt, K. et al. Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nature Med. 19, 760–765 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Gu, C. et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307, 265–268 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Pecho-Vrieseling, E., Sigrist, M., Yoshida, Y., Jessell, T. M. & Arber, S. Specificity of sensory-motor connections encoded by Sema3e-PlexinD1 recognition. Nature 459, 842–846 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Choi, Y. I. et al. PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. Immunity 29, 888–898 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Holl, E. K. et al. Plexin-D1 is a novel regulator of germinal centers and humoral immune responses. J. Immunol. 186, 5603–5611 (2011).

    Article  CAS  PubMed  Google Scholar 

  158. Sahay, A., Molliver, M. E., Ginty, D. D. & Kolodkin, A. L. Semaphorin 3F is critical for development of limbic system circuitry and is required in neurons for selective CNS axon guidance events. J. Neurosci. 23, 6671–6680 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ito, K. et al. Semaphorin 3F confines ventral tangential migration of lateral olfactory tract neurons onto the telencephalon surface. J. Neurosci. 28, 4414–4422 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tran, T. S. et al. Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462, 1065–1069 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kutschera, S. et al. Differential endothelial transcriptomics identifies semaphorin 3G as a vascular class 3 semaphorin. Arterioscler. Thromb. Vasc. Biol. 31, 151–159 (2011).

    Article  CAS  PubMed  Google Scholar 

  162. Toyofuku, T. et al. Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. EMBO J. 26, 1373–1384 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Nakagawa, Y. et al. Identification of semaphorin 4B as a negative regulator of basophil-mediated immune responses. J. Immunol. 186, 2881–2888 (2011).

    Article  CAS  PubMed  Google Scholar 

  164. Maier, V. et al. Semaphorin 4C and 4G are ligands of Plexin-B2 required in cerebellar development. Mol. Cell. Neurosci. 46, 419–431 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Shi, W. et al. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13, 633–642 (2000).

    Article  CAS  PubMed  Google Scholar 

  166. Witherden, D. A. et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 37, 314–325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhu, L. et al. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc. Natl Acad. Sci. USA 104, 1621–1626 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Fiore, R., Rahim, B., Christoffels, V. M., Moorman, A. F. & Puschel, A. W. Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system. Mol. Cell. Biol. 25, 2310–2319 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Matsuoka, R. L. et al. Class 5 transmembrane semaphorins control selective mammalian retinal lamination and function. Neuron 71, 460–473 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Renaud, J. et al. Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells. Nature Neurosci. 11, 440–449 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Bernard, F. et al. Role of transmembrane semaphorin Sema6A in oligodendrocyte differentiation and myelination. Glia 60, 1590–1604 (2012).

    Article  PubMed  Google Scholar 

  172. Kerjan, G. et al. The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nature Neurosci. 8, 1516–1524 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Tawarayama, H., Yoshida, Y., Suto, F., Mitchell, K. J. & Fujisawa, H. Roles of semaphorin-6B and plexin-A2 in lamina-restricted projection of hippocampal mossy fibers. J. Neurosci. 30, 7049–7060 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Kuwajima, T. et al. Optic chiasm presentation of Semaphorin6D in the context of Plexin-A1 and Nr-CAM promotes retinal axon midline crossing. Neuron 74, 676–690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Morote-Garcia, J. C., Napiwotzky, D., Kohler, D. & Rosenberger, P. Endothelial Semaphorin 7A promotes neutrophil migration during hypoxia. Proc. Natl Acad. Sci. USA 109, 14146–14151 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yoshida, Y., Han, B., Mendelsohn, M. & Jessell, T. M. PlexinA1 signaling directs the segregation of proprioceptive sensory axons in the developing spinal cord. Neuron 52, 775–788 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Suto, F. et al. Interactions between plexin-A2, plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron 53, 535–547 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. Toyofuku, T. et al. Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells. Dev. Biol. 321, 251–262 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. Cheng, H. J. et al. Plexin-A3 mediates semaphorin signaling and regulates the development of hippocampal axonal projections. Neuron 32, 249–263 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Yaron, A., Huang, P. H., Cheng, H. J. & Tessier-Lavigne, M. Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron 45, 513–523 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Suto, F. et al. Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J. Neurosci. 25, 3628–3637 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Yamamoto, M. et al. Plexin-A4 negatively regulates T lymphocyte responses. Int. Immunol. 20, 413–420 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Deng, S. et al. Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo. J. Neurosci. 27, 6333–6347 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Giacobini, P. et al. Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex. J. Cell Biol. 183, 555–566 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Friedel, R. H. et al. Plexin-B2 controls the development of cerebellar granule cells. J. Neurosci. 27, 3921–3932 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Perala, N. et al. Sema4C-Plexin B2 signalling modulates ureteric branching in developing kidney. Differentiation 81, 81–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Hirschberg, A. et al. Gene deletion mutants reveal a role for semaphorin receptors of the plexin-B family in mechanisms underlying corticogenesis. Mol. Cell. Biol. 30, 764–780 (2010).

    Article  CAS  PubMed  Google Scholar 

  188. Saha, B., Ypsilanti, A. R., Boutin, C., Cremer, H. & Chedotal, A. Plexin-B2 regulates the proliferation and migration of neuroblasts in the postnatal and adult subventricular zone. J. Neurosci. 32, 16892–16905 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Worzfeld, T. et al. Mice lacking Plexin-B3 display normal CNS morphology and behaviour. Mol. Cell. Neurosci. 42, 372–381 (2009).

    Article  CAS  PubMed  Google Scholar 

  190. Xu, C. & Fan, C. M. Allocation of paraventricular and supraoptic neurons requires Sim1 function: a role for a Sim1 downstream gene PlexinC1. Mol. Endocrinol. 21, 1234–1245 (2007).

    Article  CAS  PubMed  Google Scholar 

  191. Gitler, A. D., Lu, M. M. & Epstein, J. A. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev. Cell 7, 107–116 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Zhang, Y. et al. Tie2Cre-mediated inactivation of plexinD1 results in congenital heart, vascular and skeletal defects. Dev. Biol. 325, 82–93 (2009).

    Article  CAS  PubMed  Google Scholar 

  193. Zhu, L. et al. Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1039–1045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Yukawa, K. et al. Deletion of Sema4D gene reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Int. J. Mol. Med. 26, 39–44 (2010).

    Article  PubMed  Google Scholar 

  195. Li, M. et al. CD100 enhances dendritic cell and CD4+ cell activation leading to pathogenetic humoral responses and immune complex glomerulonephritis. J. Immunol. 177, 3406–3412 (2006).

    Article  CAS  PubMed  Google Scholar 

  196. Li, M. et al. Endogenous CD100 promotes glomerular injury and macrophage recruitment in experimental crescentic glomerulonephritis. Immunology 128, 114–122 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Shanks, K. et al. Neuroimmune semaphorin 4D is necessary for optimal lung allergic inflammation. Mol. Immunol. 56, 480–487 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Kigel, B., Rabinowicz, N., Varshavsky, A., Kessler, O. & Neufeld, G. Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 118, 4285–4296 (2011).

    Article  CAS  PubMed  Google Scholar 

  199. Garcia-Areas, R. et al. Semaphorin 7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice. Front. Physiol. 5, 17 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Sultana, H. et al. Semaphorin 7A contributes to West Nile virus pathogenesis through TGF-β1/ Smad6 signaling. J. Immunol. 189, 3150–3158 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Hayashi, M. et al. Intrathecally administered Sema3A protein attenuates neuropathic pain behavior in rats with chronic constriction injury of the sciatic nerve. Neurosci. Res. 69, 17–24 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Vadivel, A. et al. The axonal guidance cue semaphorin 3C contributes to alveolar growth and repair. PLoS ONE 8, e67225 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Rogalewski, A. et al. Semaphorin 6A improves functional recovery in conjunction with motor training after cerebral ischemia. PLoS ONE 5, e10737 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Namavari, A. et al. Semaphorin 7a links nerve regeneration and inflammation in the cornea. Invest. Ophthalmol. Vis. Sci. 53, 4575–4585 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Ludwigstr. 43, Bad Nauheim, 61231, Germany

    Thomas Worzfeld & Stefan Offermanns

  2. Institute of Pharmacology, University of Marburg, Karl-von-Frisch-Str. 1, Marburg, 35043, Germany

    Thomas Worzfeld

  3. Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany

    Stefan Offermanns

Authors
  1. Thomas Worzfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefan Offermanns
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Thomas Worzfeld or Stefan Offermanns.

Ethics declarations

Competing interests

T.W. and S.O. hold a patent on B-type plexin antagonists and uses thereof.

Related links

PowerPoint slides

Glossary

Angiogenesis

Process by which new blood vessels form from pre-existing vessels.

β-propeller

Type of protein architecture characterized by several blade-shaped sheets that each typically consist of four antiparallel β-strands.

GTPase-activating protein

(GAPs). Protein that binds to activated GTP-bound guanine nucleotide-binding proteins and stimulates their GTPase activity, thereby, in most cases, terminating signalling activity.

PDZ domain

Protein domain of 80–90 amino acids that binds to a short region of the carboxyl terminus of other proteins.

Guanine nucleotide exchange factors

(GEFs). Group of proteins that bind to guanine nucleotide-binding proteins and stimulate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP), usually leading to activation of signalling.

Epithelial–mesenchymal transition

(EMT). Process by which epithelial cells acquire migratory and invasive properties and increase their metastatic potential.

Experimental autoimmune encephalomyelitis

(EAE). Animal model resembling the human disease multiple sclerosis.

Microglia

Resident macrophages of the central nervous system.

Atopic dermatitis

Relapsing skin disorder, often caused by allergic reactions.

Osteoporosis

Bone disorder characterized by decreased bone mass and density.

Vitreous humour

Gel that fills the space between the retina and the lens of the eyeball.

Oligodendrocyte

Type of glial cell which forms a myelin sheath and thereby provides support and insulation to the long projections (axons) of nerve cells.

Pyramidotomy

Surgical procedure by which the corticospinal tract — which conducts impulses from the brain to the spinal cord and thereby allows the execution of precise voluntary movements — is severed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Worzfeld, T., Offermanns, S. Semaphorins and plexins as therapeutic targets. Nat Rev Drug Discov 13, 603–621 (2014). https://doi.org/10.1038/nrd4337

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4337

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer